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Role of Smooth Muscle cGMP/cGKI Signaling in Murine Vascular Restenosis.

Lukowski R, Weinmeister P, Bernhard D, Feil S, Gotthardt M, Herz J, Massberg S, Zernecke A, Weber C, Hofmann F, Feil R

Institut für Pharmakologie und Toxikologie, TU München, Germany; Interfakultäres Institut für Biochemie, Universität Tübingen, Germany; Max-Delbrück-Centrum für Molekulare Medizin, Berlin-Buch, Germany; Department of Molecular Genetics, UT Southwestern, Dallas, Tex; Deutsches Herzzentrum, TU München, Germany; and Institut für Kardiovaskuläre Molekularbiologie, RWTH Aachen, Germany.

Background-Nitric oxide (NO) is of crucial importance for smooth muscle cell (SMC) function and exerts numerous, and sometimes opposing, effects on vascular restenosis. Although cGMP-dependent protein kinase type I (cGKI) is a principal effector of NO, the molecular pathway of vascular NO signaling in restenosis is unclear. The purpose of this study was to examine the functional role of the smooth muscle cGMP/cGKI signaling cascade in restenosis of vessels. METHODS AND RESULTS: Tissue-specific mouse mutants were generated in which the cGKI protein was ablated in SMCs. We investigated whether the absence of cGKI in SMCs would affect vascular remodeling after carotid ligation or removal of the endothelium. No differences were detected between the tissue-specific cGKI mutants and control mice at different time points after vascular injury on a normolipidemic or apoE-deficient background. In line with these results, chronic drug treatment of injured control mice with the phosphodiesterase-5 inhibitor sildenafil elevated cGMP levels but had no influence on the ligation-induced remodeling. CONCLUSIONS: The genetic and pharmacological manipulation of the cGMP/cGKI signaling indicates that this pathway is not involved in the protective effects of NO, suggesting that NO affects vascular remodeling during restenosis via alternative mechanisms.

Published 18 April 2008 in Arterioscler Thromb Vasc Biol.
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